EP0409452A1 - Einen Zink-Komplex enthaltende Arzneimittel - Google Patents

Einen Zink-Komplex enthaltende Arzneimittel Download PDF

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Publication number: EP0409452A1
Authority: EP; European Patent Office
Prior art keywords: desferrioxamine; penicillamine; complex; zinc; combination
Prior art date: 1989-07-19
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Granted

Application number

EP90307400A

Other languages

English (en)

French (fr)

Other versions

EP0409452B1 (de

Inventor

Mordechai Chevion

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Yissum Research Development Co of Hebrew University of Jerusalem

Original Assignee

Yissum Research Development Co of Hebrew University of Jerusalem

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1989-07-19

Filing date

1990-07-06

Publication date

1991-01-23

1990-07-06 Application filed by Yissum Research Development Co of Hebrew University of Jerusalem filed Critical Yissum Research Development Co of Hebrew University of Jerusalem

1990-07-06 Priority to AT90307400T priority Critical patent/ATE101594T1/de

1991-01-23 Publication of EP0409452A1 publication Critical patent/EP0409452A1/de

1994-02-16 Application granted granted Critical

1994-02-16 Publication of EP0409452B1 publication Critical patent/EP0409452B1/de

2010-07-06 Anticipated expiration legal-status Critical

Status Expired - Lifetime legal-status Critical Current

Links

239000011701 zinc Substances 0.000 title claims abstract description 56
HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 title claims abstract description 27
229910052725 zinc Inorganic materials 0.000 title claims abstract description 27
239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 14
UBQYURCVBFRUQT-UHFFFAOYSA-N N-benzoyl-Ferrioxamine B Chemical compound CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN UBQYURCVBFRUQT-UHFFFAOYSA-N 0.000 claims abstract description 55
229960000958 deferoxamine Drugs 0.000 claims abstract description 28
229960001639 penicillamine Drugs 0.000 claims abstract description 28
LJRDOKAZOAKLDU-UDXJMMFXSA-N (2s,3s,4r,5r,6r)-5-amino-2-(aminomethyl)-6-[(2r,3s,4r,5s)-5-[(1r,2r,3s,5r,6s)-3,5-diamino-2-[(2s,3r,4r,5s,6r)-3-amino-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-hydroxycyclohexyl]oxy-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl]oxyoxane-3,4-diol;sulfuric ac Chemical compound OS(O)(=O)=O.N[C@@H]1[C@@H](O)[C@H](O)[C@H](CN)O[C@@H]1O[C@H]1[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](N)C[C@@H](N)[C@@H]2O)O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)N)O[C@@H]1CO LJRDOKAZOAKLDU-UDXJMMFXSA-N 0.000 claims abstract description 23
239000004480 active ingredient Substances 0.000 claims abstract description 11
XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 36
229910052742 iron Inorganic materials 0.000 claims description 18
JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 18
150000003254 radicals Chemical class 0.000 claims description 13
239000011592 zinc chloride Substances 0.000 claims description 12
235000005074 zinc chloride Nutrition 0.000 claims description 12
FIKAKWIAUPDISJ-UHFFFAOYSA-L paraquat dichloride Chemical compound [Cl-].[Cl-].C1=C[N+](C)=CC=C1C1=CC=[N+](C)C=C1 FIKAKWIAUPDISJ-UHFFFAOYSA-L 0.000 claims description 11
231100000419 toxicity Toxicity 0.000 claims description 6
230000001988 toxicity Effects 0.000 claims description 6
230000006378 damage Effects 0.000 claims description 5
238000002347 injection Methods 0.000 claims description 5
239000007924 injection Substances 0.000 claims description 5
210000002216 heart Anatomy 0.000 claims description 4
230000001575 pathological effect Effects 0.000 claims description 3
102000012437 Copper-Transporting ATPases Human genes 0.000 claims description 2
208000018565 Hemochromatosis Diseases 0.000 claims description 2
208000002972 Hepatolenticular Degeneration Diseases 0.000 claims description 2
208000018839 Wilson disease Diseases 0.000 claims description 2
230000000302 ischemic effect Effects 0.000 claims description 2
239000000644 isotonic solution Substances 0.000 claims description 2
238000004519 manufacturing process Methods 0.000 claims description 2
208000027418 Wounds and injury Diseases 0.000 claims 1
210000004556 brain Anatomy 0.000 claims 1
208000014674 injury Diseases 0.000 claims 1
210000003734 kidney Anatomy 0.000 claims 1
229940099217 desferal Drugs 0.000 description 25
239000000243 solution Substances 0.000 description 13
RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 12
229910052802 copper Inorganic materials 0.000 description 12
239000010949 copper Substances 0.000 description 12
239000000203 mixture Substances 0.000 description 8
210000004027 cell Anatomy 0.000 description 6
239000012153 distilled water Substances 0.000 description 6
229940079593 drug Drugs 0.000 description 6
239000003814 drug Substances 0.000 description 6
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
VVNCNSJFMMFHPL-VKHMYHEASA-N D-penicillamine Chemical compound CC(C)(S)[C@@H](N)C(O)=O VVNCNSJFMMFHPL-VKHMYHEASA-N 0.000 description 5
101001057427 Methanocaldococcus jannaschii (strain ATCC 43067 / DSM 2661 / JAL-1 / JCM 10045 / NBRC 100440) Iron-sulfur flavoprotein MJ1083 Proteins 0.000 description 5
229910052751 metal Inorganic materials 0.000 description 5
239000002184 metal Substances 0.000 description 5
239000000825 pharmaceutical preparation Substances 0.000 description 5
241000699670 Mus sp. Species 0.000 description 4
206010003119 arrhythmia Diseases 0.000 description 4
230000006793 arrhythmia Effects 0.000 description 4
230000001413 cellular effect Effects 0.000 description 4
IYRGXJIJGHOCFS-UHFFFAOYSA-N neocuproine Chemical compound C1=C(C)N=C2C3=NC(C)=CC=C3C=CC2=C1 IYRGXJIJGHOCFS-UHFFFAOYSA-N 0.000 description 4
230000003078 antioxidant effect Effects 0.000 description 3
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
230000027455 binding Effects 0.000 description 3
238000009739 binding Methods 0.000 description 3
239000002738 chelating agent Substances 0.000 description 3
238000002474 experimental method Methods 0.000 description 3
230000001404 mediated effect Effects 0.000 description 3
150000002739 metals Chemical class 0.000 description 3
238000000034 method Methods 0.000 description 3
229910052760 oxygen Inorganic materials 0.000 description 3
239000001301 oxygen Substances 0.000 description 3
238000002360 preparation method Methods 0.000 description 3
230000010410 reperfusion Effects 0.000 description 3
239000007787 solid Substances 0.000 description 3
239000008174 sterile solution Substances 0.000 description 3
241000588724 Escherichia coli Species 0.000 description 2
VTLYFUHAOXGGBS-UHFFFAOYSA-N Fe3+ Chemical compound [Fe+3] VTLYFUHAOXGGBS-UHFFFAOYSA-N 0.000 description 2
WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
229910021578 Iron(III) chloride Inorganic materials 0.000 description 2
241001465754 Metazoa Species 0.000 description 2
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
230000002708 enhancing effect Effects 0.000 description 2
239000008103 glucose Substances 0.000 description 2
210000003494 hepatocyte Anatomy 0.000 description 2
230000035987 intoxication Effects 0.000 description 2
231100000566 intoxication Toxicity 0.000 description 2
230000003834 intracellular effect Effects 0.000 description 2
RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 2
MGFYIUFZLHCRTH-UHFFFAOYSA-N nitrilotriacetic acid Chemical compound OC(=O)CN(CC(O)=O)CC(O)=O MGFYIUFZLHCRTH-UHFFFAOYSA-N 0.000 description 2
ZFRKQXVRDFCRJG-UHFFFAOYSA-N skatole Chemical compound C1=CC=C2C(C)=CNC2=C1 ZFRKQXVRDFCRJG-UHFFFAOYSA-N 0.000 description 2
239000011780 sodium chloride Substances 0.000 description 2
230000000451 tissue damage Effects 0.000 description 2
231100000827 tissue damage Toxicity 0.000 description 2
229910052723 transition metal Inorganic materials 0.000 description 2
150000003624 transition metals Chemical class 0.000 description 2
YZYKBQUWMPUVEN-UHFFFAOYSA-N zafuleptine Chemical compound OC(=O)CCCCCC(C(C)C)NCC1=CC=C(F)C=C1 YZYKBQUWMPUVEN-UHFFFAOYSA-N 0.000 description 2
RZLVQBNCHSJZPX-UHFFFAOYSA-L zinc sulfate heptahydrate Chemical compound O.O.O.O.O.O.O.[Zn+2].[O-]S([O-])(=O)=O RZLVQBNCHSJZPX-UHFFFAOYSA-L 0.000 description 2
JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 1
208000013875 Heart injury Diseases 0.000 description 1
206010058156 Reperfusion arrhythmia Diseases 0.000 description 1
206010063837 Reperfusion injury Diseases 0.000 description 1
PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 description 1
238000002835 absorbance Methods 0.000 description 1
239000003963 antioxidant agent Substances 0.000 description 1
235000006708 antioxidants Nutrition 0.000 description 1
230000001580 bacterial effect Effects 0.000 description 1
230000004888 barrier function Effects 0.000 description 1
230000009286 beneficial effect Effects 0.000 description 1
230000008901 benefit Effects 0.000 description 1
239000011230 binding agent Substances 0.000 description 1
230000015572 biosynthetic process Effects 0.000 description 1
239000002775 capsule Substances 0.000 description 1
230000003683 cardiac damage Effects 0.000 description 1
230000009920 chelation Effects 0.000 description 1
238000013270 controlled release Methods 0.000 description 1
238000001816 cooling Methods 0.000 description 1
ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
230000001419 dependent effect Effects 0.000 description 1
235000015872 dietary supplement Nutrition 0.000 description 1
238000006073 displacement reaction Methods 0.000 description 1
230000000694 effects Effects 0.000 description 1
SRMBQCVUAVULDJ-UHFFFAOYSA-N ferrioxamine b Chemical compound [Fe+3].CC(=O)N([O-])CCCCCNC(=O)CCC(=O)N([O-])CCCCCNC(=O)CCC(=O)N([O-])CCCCCN SRMBQCVUAVULDJ-UHFFFAOYSA-N 0.000 description 1
238000009472 formulation Methods 0.000 description 1
239000007903 gelatin capsule Substances 0.000 description 1
HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
238000010253 intravenous injection Methods 0.000 description 1
230000010438 iron metabolism Effects 0.000 description 1
208000037906 ischaemic injury Diseases 0.000 description 1
208000028867 ischemia Diseases 0.000 description 1
239000003446 ligand Substances 0.000 description 1
230000007246 mechanism Effects 0.000 description 1
239000012528 membrane Substances 0.000 description 1
230000004048 modification Effects 0.000 description 1
238000012986 modification Methods 0.000 description 1
-1 on one hand Chemical compound 0.000 description 1
230000035515 penetration Effects 0.000 description 1
230000035699 permeability Effects 0.000 description 1
230000008569 process Effects 0.000 description 1
230000001681 protective effect Effects 0.000 description 1
241000894007 species Species 0.000 description 1
238000001228 spectrum Methods 0.000 description 1
230000006641 stabilisation Effects 0.000 description 1
238000011105 stabilization Methods 0.000 description 1
230000001629 suppression Effects 0.000 description 1
CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 1
208000037816 tissue injury Diseases 0.000 description 1
239000011573 trace mineral Substances 0.000 description 1
235000013619 trace mineral Nutrition 0.000 description 1
230000002861 ventricular Effects 0.000 description 1
150000003751 zinc Chemical class 0.000 description 1
229910000368 zinc sulfate Inorganic materials 0.000 description 1
NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 1
239000011686 zinc sulphate Substances 0.000 description 1
235000009529 zinc sulphate Nutrition 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/30—Zinc; Compounds thereof
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms

Definitions

the present invention relates to a pharmaceutical composition containing a zinc complex as active ingredient therein. More particularly the present invention relates to pharmaceutical preparations which are effective against iron-mediated damage, said preparations being based on zinc complexes with desferrioxamine B or with penicillamine.
Redox-active iron and copper have been demonstrated to be responsible for tissue damage in ischemia and reperfusion injury, thallesemia, hemochromatosis and Wilson disease. Furthermore, in a wide variety of pathologic states the causative role of free radicals has been proposed. These metals can readily serve as effective mediators enhancing free radical-induced damage, and thus, have been incriminated as a major responsible species for tissue injury. (M. Chevion: A site specific mechanism for free radical induced biological damage: The essential role of redox active transition metals. Free Radical for Biology and Medicine, 5(1), 27-37, 1988).
neocuproine a chelator that effectively binds iron and copper and easily penetrates into cells, provides marked protection against ischemic-induced arrhythmias in the isolated rat heart using the Langendoff configuration.
neocuproine a chelator that effectively binds iron and copper and easily penetrates into cells
Langendoff configuration Y.J. Appelbaum, G. Uretsky and M. Chevion: The protective effect of neocuproine on cardiac injury induced by oxygen active species in the presence of copper sulphate. Journal of Molecular and Cellular Cardiology 19 (Supp. III) Abstract #8, 1987; J. Kuvin, Y.J. Appelbaum, M. Chevion, J.B. Borman and G.
Uretzky Role of oxygen free radicals in reperfusion induced arrhythmias: protection by neocuproine. Journal of Molecular and Cellular Cardiology, 19 (Supp. III), Abstract #150, 1987, Y.J. Appelbaum, J. Kuvin, J.B. Borman, G. Uretzky and M. Chevion: Role of oxygen free radicals in reperfusion-induced arrhythmias: protection by neocuproine. Free Radicals in Biology and Medicine, 8, 133-143, 1990).
the complex Zn-desferrioxamine possesses characteristics which markedly improve the pharmaceutical efficacy of Desferal. This is achieved by markedly enhancing its permeability into cells, and by the consequent significant increase of its capacity to bind intracellular iron and copper. In these chelates the transition metals are not redox-active and cannot mediate free radical production. Concomitantly with the binding of copper and iron, "free" zinc is released from its complex with Desferal or penicillamine, in a controlled mode that is fully dependent on the level of cell saturation with "free" iron and copper.
Zn-desferrioxamine complex is highly permeable, and thus, can be administered orally, providing a prominent advantage over the current procedures for administering Desferal. This is also true for the complex with penicillamine, which is usually given per os .
the present invention provides a pharmaceutical composition
a pharmaceutical composition comprising a zinc complex of desferrioxamine or penicillamine as active ingredient therein in combination with a pharmacologically acceptable carrier.
the relative stability constants for the complexes of desferrioxamine with Fe(III), Cu(II) and Zn(II) are 1031, 1014 and 1011 respectively.
the Zn-desferrioxamine complex exchanges the Zn with iron or copper.
the newly released zinc could have an additional beneficial anti-oxidant effect, as has already been shown in a few systems such as described, e.g., by D.E. Copper, D.E. Richardson and R.J. Cousins: Zinc suppression of free radicals induced in cultures of rat hepatocytes by iron, t-butyl hydroperoxide and 3-methylindole, Proceedings of the Society for Experimental Biology and Medicine 189, 100-109, 1988.
the present preparations should contain the following components:
Example 1 Zn/Desferal complex (MJC-1)
Example 2 Zn-Desferal complex (MCJ-2)
Example 3 Zn/Desferal complex (MCJ-3)
D-penicillamine (Aldrich Chemical Co., Inc.) 30 mM in doubly distilled water is mixed with equal volume of 30 mM ZnC12 (Aldrich Chemical Co., Inc.). The mixture is heated to 45°C for 30 minutes, cooled and the complex Zn/penicillamine (1.0:1.0)is formed.
Example 9 Pharmaceutical preparation of Zn/Desferal complex for i.v. injection.
a zinc chloride solution (7.6 mM) in sterile saline is prepared by dissolving 1.043 gm of high purity zinc chloride (Aldrich Chemical Co., Inc.) in one liter of saline, autoclaving and cooling to room temperature. 10 ml of the zinc chloride sterile solution is added to a vial of 500 mg of Desferal, the mixture is shaken until the contents are completely dissolved and used for either a bolus or continuous injection.
Example 10 Pharmaceutical preparation of Zn/Desferal complex for oral administration
Example 11 Pharmaceutical preparation of Zn/pencillamine complex oral administration.
D-penicillamine 250 mg is dissolved in doubly distilled water, 228.3 mg zinc chloride are added, and the solution is heated to 40 o C for 45 minutes, cooled to room temperature and then lyophilize-dried. The solid is finely pulverized and inserted into a commercial gelatin capsule.
Example 12 Pharmaceutical preparation of Zn/Pencillamine complex for oral administration
Example 13 MCJ-3 protects against cardiac damage to the isolated rat heart in the Langendorff configuration.
Example 14 MCJ-2 protects bacterial cells against copper-mediated paraquat-induced killing.
Example 15 MCJ-2 protects against paraquat toxicity in Balb C male mice
mice Groups of 10 animals were injected with 35 mg/kg paraquat which lead to death in all animals within 4-5 days. A course of treatment of the mice with MCJ-2 lead to 20-30% survivors. The course of treatment included injection of the drug i.p. at 1 hour following intoxication with paraquat (25 mg/kg), followed by 3 injections of 50 mg/kg every 8 hours. The experiments and analysis were conducted in an analogous mode to that described in R. Kohen and M. Chevion: Paraquat toxicity is enhanced by iron and inhibited by desferrioxamine in laboratory mice. Biochemical Pharmacology 34, 1841-1843, 1985.
Example 16 Displacement of zinc within Zn/desferrioxamine complex by iron taken.
Zn/desferrioxamine complex (0.2 mM) was prepared and its spectrum taken. Small volume aliquots of ferric chloride (FeCl3, 100 mM) were added to reach a final concentration of Fe(III)0.05-0.20 mM. Spectrophotometric examination shows the immediate formation of a stoichiometric complex of ferric-desferrioxamine which has a characteristic absorbance of 425 nm.

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Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
Pharmacology & Pharmacy (AREA)
Epidemiology (AREA)
Medicinal Chemistry (AREA)
Animal Behavior & Ethology (AREA)
General Health & Medical Sciences (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)
Inorganic Chemistry (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Paper (AREA)

EP90307400A 1989-07-19 1990-07-06 Einen Zink-Komplex enthaltende Arzneimittel Expired - Lifetime EP0409452B1 (de)

Priority Applications (1)

Application Number	Priority Date	Filing Date	Title
AT90307400T ATE101594T1 (de)	1989-07-19	1990-07-06	Einen zink-komplex enthaltende arzneimittel.

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
IL91047		1989-07-19
IL91047A IL91047A (en)	1989-07-19	1989-07-19	Zinc complexes for the treatment of free radical- induced diseases

Publications (2)

Publication Number	Publication Date
EP0409452A1 true EP0409452A1 (de)	1991-01-23
EP0409452B1 EP0409452B1 (de)	1994-02-16

Family

ID=11060194

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
EP90307400A Expired - Lifetime EP0409452B1 (de)	1989-07-19	1990-07-06	Einen Zink-Komplex enthaltende Arzneimittel

Country Status (6)

Country	Link
US (1)	US5075469A (de)
EP (1)	EP0409452B1 (de)
AT (1)	ATE101594T1 (de)
DE (1)	DE69006654T2 (de)
ES (1)	ES2062375T3 (de)
IL (1)	IL91047A (de)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
WO2011021203A3 (en) *	2009-08-19	2011-04-14	Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd.	Desferrioxamine-metal complexes for the treatment of immune-related disorders

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MX12394A (es) *	1987-07-23	1993-12-01	Ciba Geigy Ag	Procedimiento par la obtencion de carbamatos de polietilenglicol.
IL106064A (en) *	1993-06-18	1997-11-20	Yissum Res Dev Co	Gallium complexes for the treatment of free radical-induced diseases
US5637311A (en) *	1995-06-29	1997-06-10	Procyte Corporation	Zinc(II) complexes and methods related thereto
US6140305A (en)	1996-04-04	2000-10-31	Bio-Rad Laboratories, Inc.	Hereditary hemochromatosis gene products
US7026116B1 (en) *	1996-04-04	2006-04-11	Bio-Rad Laboratories, Inc.	Polymorphisms in the region of the human hemochromatosis gene
US6849399B1 (en)	1996-05-23	2005-02-01	Bio-Rad Laboratories, Inc.	Methods and compositions for diagnosis and treatment of iron misregulation diseases
WO1998056814A1 (en)	1997-06-13	1998-12-17	Progenitor, Inc.	Methods and compositions for diagnosis and treatment of iron overload diseases and iron deficiency diseases
US7897800B2 (en)	2006-02-03	2011-03-01	Jr Chem, Llc	Chemical compositions and methods of making them
WO2007089267A1 (en)	2006-02-03	2007-08-09	Jr Chem, Llc	Anti-aging treatment using copper and zinc compositions
US7687650B2 (en)	2006-02-03	2010-03-30	Jr Chem, Llc	Chemical compositions and methods of making them
US7867522B2 (en)	2006-09-28	2011-01-11	Jr Chem, Llc	Method of wound/burn healing using copper-zinc compositions
US8273791B2 (en)	2008-01-04	2012-09-25	Jr Chem, Llc	Compositions, kits and regimens for the treatment of skin, especially décolletage
US20160184354A1 (en)	2009-01-23	2016-06-30	Jr Chem, Llc	Rosacea treatments and kits for performing them
US8952057B2 (en)	2011-01-11	2015-02-10	Jr Chem, Llc	Compositions for anorectal use and methods for treating anorectal disorders
MX377119B (es) *	2013-06-06	2025-03-07	Amip Llc	Un sistema de dosis no alimenticia suministrable oralmente que comprende hierro y un agente.
EP3236970B1 (de)	2014-12-22	2020-12-16	Mordechai Chevion	Neue metallkomplexe von nocardamin und deren verwendung in pharmazeutischen zusammensetzungen
KR20180105701A (ko)	2016-02-11	2018-09-28	모데차이 체비온	신경변성의 치료를 위한 방법 및 약학 조성물
JP2021521209A (ja) *	2018-04-15	2021-08-26	モデハイシェヴィオンCHEVION, Mordechai	鉄過剰症の治療のための組成物及び方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US2554690A (en) *	1944-06-13	1951-05-29	Squibb & Sons Inc	Zinc-penicillin and preparation thereof
GB1093445A (en) *	1963-12-11	1967-12-06	Ernst Albert Hermann Friedheim	Improvements in or relating to penicillamine complexes and therapeutic compositions containing these complexes
EP0325559A2 (de) *	1988-01-20	1989-07-26	Ciba-Geigy Ag	Verfahren zur Herstellung von Komplexverbindungen

1989
- 1989-07-19 IL IL91047A patent/IL91047A/xx not_active IP Right Cessation
1990
- 1990-07-06 AT AT90307400T patent/ATE101594T1/de active
- 1990-07-06 ES ES90307400T patent/ES2062375T3/es not_active Expired - Lifetime
- 1990-07-06 DE DE69006654T patent/DE69006654T2/de not_active Expired - Fee Related
- 1990-07-06 EP EP90307400A patent/EP0409452B1/de not_active Expired - Lifetime
- 1990-07-10 US US07/550,462 patent/US5075469A/en not_active Expired - Fee Related

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WO2011021203A3 (en) *	2009-08-19	2011-04-14	Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd.	Desferrioxamine-metal complexes for the treatment of immune-related disorders
US8975294B2 (en)	2009-08-19	2015-03-10	Hadasit Medical Research Services And Development Ltd.	Desferrioxamine-metal complexes for the treatment of immune-related disorders
AU2010286054B2 (en) *	2009-08-19	2016-10-27	Mordechai Chevion	Desferrioxamine-metal complexes for the treatment of immune-related disorders
US9770430B2 (en)	2009-08-19	2017-09-26	Mordechai Chevion	Desferrioxamine-metal complexes for the treatment of immune-related disorders
EP3189836A3 (de) *	2009-08-19	2017-09-27	Mordechai Chevion	Desferrioxaminmetallkomplexe und verfahren zur behandlung von immunerkrankungen
AU2016244189B2 (en) *	2009-08-19	2018-06-28	Mordechai Chevion	Desferrioxamine-metal complexes for the treatment of immune-related disorders

Also Published As

Publication number	Publication date
DE69006654T2 (de)	1994-05-26
DE69006654D1 (de)	1994-03-24
IL91047A (en)	1993-06-10
US5075469A (en)	1991-12-24
EP0409452B1 (de)	1994-02-16
ES2062375T3 (es)	1994-12-16
ATE101594T1 (de)	1994-03-15
IL91047A0 (en)	1990-02-09

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